The present invention relates generally to compositions and methods for the treatment of prostate cancer. The invention is more particularly related to polypeptides comprising at least a portion of a prostate tumor protein and to polynucleotide molecules encoding such polypeptides. Such polypeptides may be used in vaccines and pharmaceutical compositions for treatment of prostate cancer.
Prostate cancer is the most common form of cancer among males, with an estimated incidence of 30% in men over the age of 50. Overwhelming clinical evidence shows that human prostate cancer has the propensity to metastasize to bone, and the disease appears to progress inevitably from androgen dependent to androgen refractory status, leading to increased patient mortality. This prevalent disease is currently the second leading cause of cancer death among men in the U.S.
In spite of considerable research into therapies for the disease, prostate cancer remains difficult to treat. Commonly, treatment is based on surgery and/or radiation therapy, but these methods are ineffective in a significant percentage of cases. Two previously identified prostate specific proteinsxe2x80x94prostate specific antigen (PSA) and prostatic acid phosphatase (PAP)xe2x80x94have limited therapeutic and diagnostic potential. For example, PSA levels do not always correlate well with the presence of prostate cancer, being positive in a percentage of non-prostate cancer cases, including benign prostatic hyperplasia (BPH). Furthermore, PSA measurements correlate with prostate volume, and do not indicate the level of metastasis.
Accordingly, there remains a need in the art for improved vaccines and treatment methods for,prostate cancer. The present invention fulfills these needs and further provides other related advantages.
The present invention provides compounds and methods for immunotherapy of prostate cancer. In one aspect, isolated polypeptides are provided comprising at least an immunogenic portion of a prostate tumor protein or a variant thereof that differs only in one or more substitutions, deletions, additions and/or insertions, such that the ability of the variant to react with protein-specific antisera is not substantially diminished. Within certain embodiments, the prostate tumor protein comprises an amino acid sequence encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NO: 2, 3, 8-29, 41-45, 47-52, 54-65, 70, 73-74, 79, 81, 87, 90, 92, 93, 97, 103, 104, 107, 109-111, 115-160, 171, 173-175, 177, 181, 188, 191, 193, 194, 198, 203, 204, 207, 209, 220, 222-225, 227-305, 307-315, 326, 328, 330, 332, and 334, and complements of such polynucleotides.
In related aspects, isolated polynucleotides encoding the above polypeptides or portions thereof are provided. In specific embodiments, such polynucleotides may comprise a sequence provided in SEQ ID NO: 2, 3, 8-29, 41-45, 47-52, 54-65, 70, 73-74, 79, 81, 87, 90, 92, 93, 97, 103, 104, 107, 109-111, 115-160, 171, 173-175, 177, 181, 188, 191, 193, 194, 198, 203, 204, 207, 209, 220, 222-225, 227-305, 307-315, 326, 328, 330, 332, or 334. The present invention further provides expression vectors comprising the above polynucleotides and host cells transformed or transfected with such expression vectors. In preferred embodiments, the host cells are selected from the group consisting of E. coli, yeast and mammalian cells.
In another aspect, the present invention provides fusion proteins comprising at least one polypeptide as described above, in combination with a second polypeptide as described above and/or a known prostate tumor antigen. Polynucleotides encoding such fusion proteins are further provided.
The present invention also provides pharmaceutical compositions comprising one or more of the above polypeptides, or a polynucleotide molecule encoding such polypeptides, and a physiologically acceptable carrier, together with vaccines comprising one or more of such polypeptide or polynucleotide molecules in combination with a non-specific immune response enhancer.
Within other aspects, the present invention provides pharmaceutical compositions comprising (a) an antibody that specifically binds to a prostate tumor protein that comprises an amino acid sequence that is encoded by a polynucleotide sequence selected from the group consisting of (i) nucleotide sequences recited in any one of SEQ ID NOS: 2, 3, 8-29, 41-45, 47-52, 54-65, 70, 73-74, 79, 81, 87, 90, 92, 93, 97, 103, 104, 107, 109-111, 115-160, 171, 173-175, 177, 181, 188, 191, 193, 194, 198, 203, 204, 207, 209, 220, 222-225, 227-305, 307-315, 326, 328, 330, 332, or 334; and (ii) complements of the foregoing polynucleotide sequences; and (b) a physiologically acceptable carrier. Vaccines are also provided, comprising one or more such antibodies in combination with a non-specific immune response enhancer.
Within other aspects, the present invention provides pharmaceutical compositions comprising (a) a T cell that specifically reacts with a prostate tumor protein that comprises an amino acid sequence that is encoded by a polynucleotide sequence selected from the group consisting of (i) nucleotide sequences recited in any one of SEQ ID NOS: 2, 3, 8-29, 41-45, 47-52, 54-65, 70, 73-74, 79, 81, 87, 90, 92, 93, 97, 103, 104, 107, 109-111, 115-160, 171, 173-175, 177, 181, 188, 191, 193, 194, 198, 203, 204, 207, 209, 220, 222-225, 227-305, 307-315, 326, 328, 330, 332, or 334; and (ii) complements of the foregoing polynucleotide sequences; and (b) a physiologically acceptable carrier. Vaccines are also provided, comprising one or more such T cells in combination with a non-specific immune response enhancer.
In yet a further aspect, methods for the treatment of prostate cancer in a patient are provided, the methods comprising obtaining PBMC from the patient, incubating the PBMC with a polypeptide of the present invention (or a polynucleotide that encodes such a polypeptide) to provide incubated T cells and administering the incubated T cells to the patient. The present invention additionally provides methods for the treatment of prostate cancer that comprise incubating antigen presenting cells with a polypeptide of the present invention (or a polynucleotide that encodes such a polypeptide) to provide incubated antigen presenting cells and administering the incubated antigen presenting cells to the patient. In certain embodiments, the antigen presenting cells are selected from the group consisting of dendritic cells and macrophages. Compositions for the treatment of prostate cancer comprising T cells or antigen presenting cells that have been incubated with a polypeptide or polynucleotide of the present invention are also provided.
In yet another aspect, methods are provided for inhibiting the development of prostate cancer in a patient, comprising administering an effective amount of at least one of the above pharmaceutical compositions and/or vaccines.